The role of programmed cell death, or apoptosis, during the progression of oral squamous cell carcinoma (SCC) is not known. All surfaces in the oral cavity have the potential for terminal differentiation to keratinized epithelium. Differentiation of oral epithelium is believed to follow a highly regulated pathway that is similar in some ways to epidermal differentiation. This pathway begins with mitotically active, undifferentiated, Bcl-2-expressing basal cells that migrate outward, becoming terminally differentiated during a process that involves loss of Bcl-2 and induction of programmed cell death (PCD). Overexpression of apoptosis inhibitors in skin can disrupt the normal differentiation pathway and lead to skin disease and malignancy. Since oral epithelium appears to undergo a differentiation program similar to that of skin, suggests that the bcl-2 family of apoptosis genes may also play a role in oral epithelial differentiation. Expression of an apoptosis inhibitor in a well-differentiated SCC cell line delayed terminal differentiation through prevention of apoptosis. Thus, uncontrolled or inappropriate expression of this family of genes could lead to an aberrant accumulation of undifferentiated but proliferating cells which may contribute to neoplasia. The overall goal of this project is to determine whether the bcl-2 family of apoptosis genes plays a role in the progression of normal oral keratinocytes to oral SCC. The following hypothesis will be tested: In oral $CC, controlled apoptosis is disrupted by abnormal expression of the bcl-2 family of PCD/apoptosis regulator genes. The specific aims will address these questions: 1) Is there a positive correlation between expression of the bcl-2 family of apoptosis regulators and SCC tumor progression? 2) Will overexpression of apoptosis inducers moderate tumorigenicity? The long term goal of this proposal is to determine whether induction of apoptosis in SCC can reduce oral SCC tumorigenicity. Artificial induction of apoptosis and terminal differentiation may provide a potential therapeutic approach in the treatment of oral SCC.